Hypertension is a major risk factor for intracranial hemorrhage (ICH). Models of spontaneous ICH in hypertensive mice would be useful, because they would allow studies of mechanisms in genetically altered mice. Recently, the investigators developed the first two models of spontaneous ICH in hypertensive mice. The major goal of this Project is to examine mechanisms that predispose to, and protect against, ICH in hypertensive mice. The strategy is to characterize the two experimental models in relation to oxidative stress and antioxidant mechanisms, and to pursue determinants of ICH (including matrix metalloproteinases (MMPs), which are activated by oxidative stress) using genetically altered mice. First, studies are proposed to test the hypothesis that oxidative stress is associated with, and may contribute to, ICH during chronic hypertension. Oxidative stress in the brain will be examined with lucigenin in hypertensive mice with ICH. Experiments also are planned to determine whether hypertensive mice that are deficient in gp91phox, a subunit of NAD(P)H oxidase, are resistant to ICH. Second, studies are proposed to test the hypothesis that antioxidants protect against ICH during chronic hypertension. Experiments are planned to determine whether reduction of oxidative stress by tempol, or in mice that overexpress copper-zinc superoxide dismutase, protects against ICH. Studies also are planned to determine whether susceptibility to ICH is attenuated in mice that are deficient in MMP-9. The studies may provide evidence that oxidative stress acts through MMP-9 to contribute to ICH. Third, experiments are proposed to test the hypothesis that the nuclear transcription factor PPARgamma, which inhibits pro-oxidative mechanisms and expression of MMP-9, and augments anti-oxidant mechanisms, protects against ICH. Studies are planned to test the hypothesis that a pharmacologic agonist for PPAR-gamma, rosiglitazone, reduces oxidative stress and protects against ICH in hypertensive mice. Experiments also are proposed to test the hypothesis, using mice with knock-in of PPAR-gamma P465L (a loss-of-function gene variant), that endogenous PPAR-gamma protects against ICH. These studies may provide important insight into mechanisms that produce, and protect against, spontaneous ICH in hypertension, and thus may lead to novel approaches to prevent and treat ICH.